HSF4 Promotes Human Lens Epithelial Cells G1/S Arrest through Stabilizing p53

Abstract

The differentiation from constantly dividing epithelial cells into fiber cells is the key step during lens development. Failure in lens fiber cells differentiation, which requires cell proliferation inhibition and cell cycle exit, causes cataract formation. It has been discovered that HSF4 (Heat Shock Factor 4) gene mutations led to congenital and senile cataracts. And the lens of HSF4 knockout mice showed increased proliferation of epithelial cells and premature differentiation of fiber cells. However, the molecular roles that HSF4 mutations play in cataract formation remain obscure. In present study, we found that wild type HSF4 suppressed human lens epithelial cells (HLECs) proliferation by promoting G1/S arrest. We further identified that HSF4 could interact with p53 and stabilize p53 protein by inhibiting its ubiquitin degradation.The p53 transcriptional activity was also increased by HSF4. In contrast, HSF4 cataract mutants had no effects on either HLECs proliferation or p53 protein stabilization. On the other hand, the wild type HSF4 lost its ability in cell proliferation inhibition and G1/S cell cycle arrest in p53‐null H1299 cell line. Our data reveals that HSF4 may work as a switch between lens epithelial cell proliferation and fiber cell differentiation, and p53 is required in this process.